Journal articles: 'Ca2+ lysosomal'

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Wang, Wuyang, Xiaoli Zhang, Qiong Gao, Maria Lawas, Lu Yu, Xiping Cheng, Mingxue Gu, et al. "A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ stores." Journal of Cell Biology 216, no. 6 (May 3, 2017): 1715–30. http://dx.doi.org/10.1083/jcb.201612123.

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The resting membrane potential (Δψ) of the cell is negative on the cytosolic side and determined primarily by the plasma membrane’s selective permeability to K+. We show that lysosomal Δψ is set by lysosomal membrane permeabilities to Na+ and H+, but not K+, and is positive on the cytosolic side. An increase in juxta-lysosomal Ca2+ rapidly reversed lysosomal Δψ by activating a large voltage-dependent and K+-selective conductance (LysoKVCa). LysoKVCa is encoded molecularly by SLO1 proteins known for forming plasma membrane BK channels. Opening of single LysoKVCa channels is sufficient to cause the rapid, striking changes in lysosomal Δψ. Lysosomal Ca2+ stores may be refilled from endoplasmic reticulum (ER) Ca2+ via ER–lysosome membrane contact sites. We propose that LysoKVCa serves as the perilysosomal Ca2+ effector to prime lysosomes for the refilling process. Consistently, genetic ablation or pharmacological inhibition of LysoKVCa, or abolition of its Ca2+ sensitivity, blocks refilling and maintenance of lysosomal Ca2+ stores, resulting in lysosomal cholesterol accumulation and a lysosome storage phenotype.

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Rodríguez, Ana, Paul Webster, Javier Ortego, and Norma W. Andrews. "Lysosomes Behave as Ca2+-regulated Exocytic Vesicles in Fibroblasts and Epithelial Cells." Journal of Cell Biology 137, no. 1 (April 7, 1997): 93–104. http://dx.doi.org/10.1083/jcb.137.1.93.

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Lysosomes are considered to be a terminal degradative compartment of the endocytic pathway, into which transport is mostly unidirectional. However, specialized secretory vesicles regulated by Ca2+, such as neutrophil azurophil granules, mast cell–specific granules, and cytotoxic lymphocyte lytic granules, share characteristics with lysosomes that may reflect a common biogenesis. In addition, the involvement of Ca2+ transients in the invasion mechanism of the parasite Trypanosoma cruzi, which occurs by fusion of lysosomes with the plasma membrane, suggested that lysosome exocytosis might be a generalized process present in most cell types. Here we demonstrate that elevation in the intracellular free Ca2+ concentration of normal rat kidney (NRK) fibroblasts induces fusion of lysosomes with the plasma membrane. This was verified by measuring the release of the lysosomal enzyme β-hexosaminidase, the appearance on the plasma membrane of the lysosomal glycoprotein lgp120, the release of fluid-phase tracers previously loaded into lysosomes, and the release of the lysosomally processed form of cathepsin D. Exposure to the Ca2+ ionophore ionomycin or addition of Ca2+containing buffers to streptolysin O–permeabilized cells induced exocytosis of ∼10% of the total lysosomes of NRK cells. The process was also detected in other cell types such as epithelial cells and myoblasts. Lysosomal exocytosis was found to require micromolar levels of Ca2+ and to be temperature and ATP dependent, similar to Ca2+-regulated secretory mechanisms in specialized cells. These findings highlight a novel role for lysosomes in cellular membrane traffic and suggest that fusion of lysosomes with the plasma membrane may be an ubiquitous form of Ca2+-regulated exocytosis.

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Xu, Ming, Xiaoxue Li, Scott W. Walsh, Yang Zhang, Justine M. Abais, Krishna M. Boini, and Pin-Lan Li. "Intracellular two-phase Ca2+ release and apoptosis controlled by TRP-ML1 channel activity in coronary arterial myocytes." American Journal of Physiology-Cell Physiology 304, no. 5 (March 1, 2013): C458—C466. http://dx.doi.org/10.1152/ajpcell.00342.2012.

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Activation of the death receptor Fas has been reported to produce a two-phase intracellular Ca2+ release response in coronary arterial myocytes (CAMs), which consists of local Ca2+ bursts via lysosomal transient potential receptor-mucolipin 1 (TRP-ML1) channels and consequent Ca2+ release from the sarcoplasmic reticulum (SR). The present study was designed to explore the molecular mechanism by which lysosomal Ca2+ bursts are coupled with SR Ca2+ release in mouse CAMs and to determine the functional relevance of this lysosome-associated two-phase Ca2+ release to apoptosis, a common action of Fas activation with Fas ligand (FasL). By confocal microscopy, we found that transfection of CAMs with TRP-ML1 small interfering (si)RNA substantially inhibited FasL (10 ng/ml)-induced lysosome Ca2+ bursts and consequent SR Ca2+ release. In contrast, transfection of CAMs with plasmids containing a full-length TRP-ML1 gene enhanced FasL-induced two-phase Ca2+ release. We further demonstrated that FasL significantly increased the colocalization of the lysosomal marker Lamp1 with ryanodine receptor 3 and enhanced a dynamic trafficking of lysosomes to the SR. When CAMs were treated with TRP-ML1 siRNA, FasL-induced interactions between the lysosomes and SR were substantially blocked. Functionally, FasL-induced apoptosis and activation of calpain and calcineurin, the Ca2+ sensitive proteins that mediate apoptosis, were significantly attenuated by silencing TRP-ML1 gene but enhanced by overexpression of TRP-ML1 gene. These results suggest that TRP-ML1 channel-mediated lysosomal Ca2+ bursts upon FasL stimulation promote lysosome trafficking and interactions with the SR, leading to apoptosis of CAMs via a Ca2+-dependent mechanism.

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Peng, Wesley, Yvette C. Wong, and Dimitri Krainc. "Mitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1." Proceedings of the National Academy of Sciences 117, no. 32 (July 23, 2020): 19266–75. http://dx.doi.org/10.1073/pnas.2003236117.

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Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.

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Burlando, Bruno, Barbara Marchi, Isabella Panfoli, and Aldo Viarengo. "Essential role of Ca2+-dependent phospholipase A2in estradiol-induced lysosome activation." American Journal of Physiology-Cell Physiology 283, no. 5 (November 1, 2002): C1461—C1468. http://dx.doi.org/10.1152/ajpcell.00429.2001.

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The mechanism of lysosome activation by 17β-estradiol has been studied in mussel blood cells. Cell treatment with estradiol induced a sustained increase of cytosolic free Ca2+that was completely prevented by preincubating the cells with the Ca2+chelator BAPTA-AM. Estradiol treatment was also followed by destabilization of the lysosomal membranes, as detected in terms of the lysosomes' increased permeability to neutral red. The effect of estradiol on lysosomes was almost completely prevented by preincubation with the inhibitor of cytosolic Ca2+-dependent PLA2(cPLA2), arachidonyl trifluoromethyl ketone (AACOCF3), and was significantly reduced by preincubation with BAPTA-AM. In contrast, it was virtually unaffected by preincubation with the inhibitor of Ca2+-independent PLA2, ( E)-6-(bromomethylene)tetrahydro-3-(1-naphtalenyl)-2 H-pyran-2-one (BEL). The Ca2+ionophore A-23187 yielded similar effects on [Ca2+]iand lysosomes. Exposure to estradiol also resulted in cPLA2translocation from cytosol to membranes, lysosome enlargement, and increased protein degradation. These results suggest that the destabilization of lysosomal membranes following cell exposure to estradiol occurs mainly through a Ca2+-dependent mechanism involving activation of Ca2+-dependent PLA2. This mechanism promotes lysosome fusion and catabolic activities and may mediate short-term estradiol effects.

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Li, Guangbi, Dandan Huang, Jinni Hong, Owais M. Bhat, Xinxu Yuan, and Pin-Lan Li. "Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes." American Journal of Physiology-Cell Physiology 317, no. 3 (September 1, 2019): C481—C491. http://dx.doi.org/10.1152/ajpcell.00150.2019.

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The transient receptor potential mucolipin 1 (TRPML1) channel has been reported to mediate lysosomal Ca2+ release that is involved in Ca2+-dependent lysosome trafficking and autophagic flux. However, this regulatory mechanism of lysosomal TRPML1 channel activity in podocytes remains poorly understood. In the present study, we tested whether the TRPML1 channel in podocytes mediates lysosome trafficking, which is essential for multivesicular body (MVB) degradation by lysosomes. We first demonstrated the abundant expression of TRPML1 channel in podocytes. By GCaMP3 Ca2+ imaging, we characterized the lysosomal specificity of TRPML1 channel-mediated Ca2+ release in podocytes. Given the important role of acid ceramidase (AC) in lysosome function and podocyte injury, we tested whether AC regulates this TRPML1 channel-mediated Ca2+ release and consequent lysosome-dependent MVB degradation in podocytes. Pharmacologically, it was found that TRPML1 channel activity was remarkably attenuated by the AC inhibitor carmofur. Sphingosine, as an AC product, was demonstrated to induce TRPML1-mediated Ca2+ release, which was inhibited by a TRPML1 blocker, verapamil. Using a Port-a-Patch planar patch-clamp system, we found that AC-associated sphingolipids, sphingomyelin, ceramide, and sphingosine had different effects on TRPML1 channel activity in podocytes. Functionally, the inhibition of AC or blockade of TRPML1 channels was found to suppress the interaction of lysosomes and MVBs, leading to increased exosome release from podocytes. These results suggest that AC is critical for TRPML1 channel-mediated Ca2+ release, which controls lysosome-MVB interaction and exosome release in podocytes.

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McCue, Hannah V., Joanna D. Wardyn, Robert D. Burgoyne, and Lee P. Haynes. "Generation and characterization of a lysosomally targeted, genetically encoded Ca2+-sensor." Biochemical Journal 449, no. 2 (December 14, 2012): 449–57. http://dx.doi.org/10.1042/bj20120898.

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Distinct spatiotemporal Ca2+ signalling events regulate fundamental aspects of eukaryotic cell physiology. Complex Ca2+ signals can be driven by release of Ca2+ from intracellular organelles that sequester Ca2+ such as the ER (endoplasmic reticulum) or through the opening of Ca2+-permeable channels in the plasma membrane and influx of extracellular Ca2+. Late endocytic pathway compartments including late-endosomes and lysosomes have recently been observed to sequester Ca2+ to levels comparable with those found within the ER lumen. These organelles harbour ligand-gated Ca2+-release channels and evidence indicates that they can operate as Ca2+-signalling platforms. Lysosomes sequester Ca2+ to a greater extent than any other endocytic compartment, and signalling from this organelle has been postulated to provide ‘trigger’ release events that can subsequently elicit more extensive Ca2+ signals from stores including the ER. In order to investigate lysosomal-specific Ca2+ signalling a simple method for measuring lysosomal Ca2+ release is essential. In the present study we describe the generation and characterization of a genetically encoded, lysosomally targeted, cameleon sensor which is capable of registering specific Ca2+ release in response to extracellular agonists and intracellular second messengers. This probe represents a novel tool that will permit detailed investigations examining the impact of lysosomal Ca2+ handling on cellular physiology.

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Rao, Swathi K., Chau Huynh, Veronique Proux-Gillardeaux, Thierry Galli, and Norma W. Andrews. "Identification of SNAREs Involved in Synaptotagmin VII-regulated Lysosomal Exocytosis." Journal of Biological Chemistry 279, no. 19 (March 1, 2004): 20471–79. http://dx.doi.org/10.1074/jbc.m400798200.

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Ca2+-regulated exocytosis of lysosomes has been recognized recently as a ubiquitous process, important for the repair of plasma membrane wounds. Lysosomal exocytosis is regulated by synaptotagmin VII, a member of the synaptotagmin family of Ca2+-binding proteins localized on lysosomes. Here we show that Ca2+-dependent interaction of the synaptotagmin VII C2A domain with SNAP-23 is facilitated by syntaxin 4. Specific interactions also occurred in cell lysates between the plasma membrane t-SNAREs SNAP-23 and syntaxin 4 and the lysosomal v-SNARE TI-VAMP/VAMP7. Following cytosolic Ca2+elevation, SDS-resistant complexes containing SNAP-23, syntaxin 4, and TI-VAMP/VAMP7 were detected on membrane fractions. Lysosomal exocytosis was inhibited by the SNARE domains of syntaxin 4 and TI-VAMP/VAMP7 and by cleavage of SNAP-23 with botulinum neurotoxin E, thereby functionally implicating these SNAREs in Ca2+-regulated exocytosis of conventional lysosomes.

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Bakker, A. C., P. Webster, W. A. Jacob, and N. W. Andrews. "Homotypic fusion between aggregated lysosomes triggered by elevated [Ca2+]i in fibroblasts." Journal of Cell Science 110, no. 18 (September 15, 1997): 2227–38. http://dx.doi.org/10.1242/jcs.110.18.2227.

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Previous studies demonstrated that microinjection of antibodies to the cytoplasmic domain of the lysosomal glycoprotein lgp120 induces aggregation of lysosomes in NRK cells. Here we show that the antibody-clustered vesicles do not co-localize with MPR and ss-COP-containing organelles, confirming their lysosomal nature. Observations by transmission and high voltage electron microscopy indicated that, although tightly apposed to each other, aggregated lysosomes remained as separate vesicles, with an average diameter of 0.3-0.4 micron. However, when cells microinjected with antibody were exposed to the Ca2+ ionophore ionomycin, large vesicles were formed within the lysosome clusters, suggesting the occurrence of lysosome-lysosome fusion. Stereological measurements of lysosome diameters on confocal and transmission electron microscopy indicated that the large lgp120-positive vesicles could have originated from the fusion of 3 up to 15 individual lysosomes. To verify if agents that mobilize Ca2+ from intracellular stores had the same effect, anti-lgp120-microinjected cells were treated with thapsigargin, and with the receptor-mediated agonists bombesin and thrombin. Thapsigargin also induced the formation of large lgp120-containing vesicles, detected by both confocal and transmission electron microscopy. Analysis of antibody-clustered lysosomes in streptolysin O-permeabilized cells indicated that an intracellular free Ca2+ concentration of 1 microM was sufficient to trigger formation of large lysosomes.

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Flannery, Andrew R., Cecilia Czibener, and Norma W. Andrews. "Palmitoylation-dependent association with CD63 targets the Ca2+ sensor synaptotagmin VII to lysosomes." Journal of Cell Biology 191, no. 3 (November 1, 2010): 599–613. http://dx.doi.org/10.1083/jcb.201003021.

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Syt VII is a Ca2+ sensor that regulates lysosome exocytosis and plasma membrane repair. Because it lacks motifs that mediate lysosomal targeting, it is unclear how Syt VII traffics to these organelles. In this paper, we show that mutations or inhibitors that abolish palmitoylation disrupt Syt VII targeting to lysosomes, causing its retention in the Golgi complex. In macrophages, Syt VII is translocated simultaneously with the lysosomal tetraspanin CD63 from tubular lysosomes to nascent phagosomes in a Ca2+-dependent process that facilitates particle uptake. Mutations in Syt VII palmitoylation sites block trafficking of Syt VII, but not CD63, to lysosomes and phagosomes, whereas tyrosine replacement in the lysosomal targeting motif of CD63 causes both proteins to accumulate on the plasma membrane. Complexes of CD63 and Syt VII are detected only when Syt VII palmitoylation sites are intact. These findings identify palmitoylation-dependent association with the tetraspanin CD63 as the mechanism by which Syt VII is targeted to lysosomes.

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Wang, Wuyang, Qiong Gao, Meimei Yang, Xiaoli Zhang, Lu Yu, Maria Lawas, Xinran Li, et al. "Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation." Proceedings of the National Academy of Sciences 112, no. 11 (March 2, 2015): E1373—E1381. http://dx.doi.org/10.1073/pnas.1419669112.

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Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca2+ imaging and whole-lysosome patch clamping, lysosomal Ca2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na+-selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann–Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca2+ signaling.

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Zhang, Fan, Ming Xu, Wei-Qing Han, and Pin-Lan Li. "Reconstitution of lysosomal NAADP-TRP-ML1 signaling pathway and its function in TRP-ML1−/− cells." American Journal of Physiology-Cell Physiology 301, no. 2 (August 2011): C421—C430. http://dx.doi.org/10.1152/ajpcell.00393.2010.

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It is well known that the mutation of TRP-ML1 (transient receptor potential-mucolipin-1) causes mucolipidosis IV, a lysosomal storage disease. Given that lysosomal nicotinic acid adenine dinucleotide phosphate (NAADP)-Ca2+ release channel activity is associated with TRP-ML1, the present study was designed to test the hypothesis that NAADP regulates lysosome function via activation of TRP-ML1 channel activity. Using lysosomal preparations from wild-type (TRP-ML1+/+) human fibroblasts, channel reconstitution experiments demonstrated that NAADP (0.01–1.0 μM) produced a concentration-dependent increase in TRP-ML1 channel activity. This NAADP-induced activation of TRP-ML1 channels could not be observed in lysosomes from TRP-ML1−/− cells, but was restored by introducing a TRP-ML1 transgene into these cells. Microscopic Ca2+ fluorescence imaging showed that NAADP significantly increased intracellular Ca2+ concentration to 302.4 ± 74.28 nM (vs. 180 ± 44.13 nM of the basal) in TRP-ML1+/+ cells, but it had no effect in TRP-ML1−/− cells. If a TRP-ML1 gene was transfected into TRP-ML1−/− cells, the Ca2+ response to NAADP was restored to the level comparable to TRP-ML1+/+ cells. Functionally, confocal microscopy revealed that NAADP significantly enhanced the dynamic interaction of endosomes and lysosomes and the lipid delivery to lysosomes in TRP-ML1+/+ cells. This functional action of NAADP was abolished in TRP-ML1−/− cells, but restored after TRP-ML1 gene was rescued in these cells. Our results suggest that NAADP increases lysosomal TRP-ML1 channel activity to release Ca2+, which promotes the interaction of endosomes and lysosomes and thereby regulates lipid transport to lysosomes. Failure of NAADP-TRP-ML1 signaling may be one of the important mechanisms resulting in intracellular lipid trafficking disorder and consequent mucolipidosis.

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Wu, Yi, Peng Huang, and Xian-Ping Dong. "Lysosomal Calcium Channels in Autophagy and Cancer." Cancers 13, no. 6 (March 15, 2021): 1299. http://dx.doi.org/10.3390/cancers13061299.

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Ca2+ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca2+ signaling is regulated by both extracellular Ca2+ entry and Ca2+ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca2+ store that provides Ca2+ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca2+. In lysosomal Ca2+-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca2+ stores and their roles in autophagy and human cancer progression.

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Zhong, Xi Zoë, Yuanjie Zou, Xue Sun, Gaofeng Dong, Qi Cao, Aditya Pandey, Jan K. Rainey, Xiaojuan Zhu, and Xian-Ping Dong. "Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases." Journal of Biological Chemistry 292, no. 8 (January 13, 2017): 3445–55. http://dx.doi.org/10.1074/jbc.m116.743963.

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Impaired adenosine homeostasis has been associated with numerous human diseases. Lysosomes are referred to as the cellular recycling centers that generate adenosine by breaking down nucleic acids or ATP. Recent studies have suggested that lysosomal adenosine overload causes lysosome defects that phenocopy patients with mutations in transient receptor potential channel mucolipin-1 (TRPML1), a lysosomal Ca2+ channel, suggesting that lysosomal adenosine overload may impair TRPML1 and then lead to subsequent lysosomal dysfunction. In this study, we demonstrate that lysosomal adenosine is elevated by deleting adenosine deaminase (ADA), an enzyme responsible for adenosine degradation. We also show that lysosomal adenosine accumulation inhibits TRPML1, which is rescued by overexpressing ENT3, the adenosine transporter situated in the lysosome membrane. Moreover, ADA deficiency results in lysosome enlargement, alkalinization, and dysfunction. These are rescued by activating TRPML1. Importantly, ADA-deficient B-lymphocytes are more vulnerable to oxidative stress, and this was rescued by TRPML1 activation. Our data suggest that lysosomal adenosine accumulation impairs lysosome function by inhibiting TRPML1 and subsequently leads to cell death in B-lymphocytes. Activating TRPML1 could be a new therapeutic strategy for those diseases.

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Baram, Dana, Roberto Adachi, Ora Medalia, Michael Tuvim, Burton F. Dickey, Yoseph A. Mekori, and Ronit Sagi-Eisenberg. "Synaptotagmin II Negatively Regulates Ca2+-triggered Exocytosis of Lysosomes in Mast Cells." Journal of Experimental Medicine 189, no. 10 (May 17, 1999): 1649–58. http://dx.doi.org/10.1084/jem.189.10.1649.

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Synaptotagmins (Syts) I and II are believed to act as Ca2+ sensors in the control of neurotransmission. Here we demonstrate that mast cells express Syt II in their lysosomal fraction. We further show that activation of mast cells by either aggregation of FcεRI or by Ca2+ ionophores results in exocytosis of lysosomes, in addition to the well documented exocytosis of their secretory granules. Syt II directly regulates lysosomal exocytosis, whereby overexpression of Syt II inhibited Ca2+-triggered release of the lysosomal processed form of cathepsin D, whereas suppression of Syt II expression markedly potentiated this release. These findings provide evidence for a novel function of Syt II in negatively regulating Ca2+-triggered exocytosis of lysosomes, and suggest that Syt II–regulated secretion from lysosomes may play an important role in mast cell biology.

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McBrayer, MaryKate, and Ralph A. Nixon. "Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime." Biochemical Society Transactions 41, no. 6 (November 20, 2013): 1495–502. http://dx.doi.org/10.1042/bst20130201.

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Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.

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Pandey, Vinita, Chia-Chen Chuang, Alexander M. Lewis, Parvinder K. Aley, Eugen Brailoiu, Nae J. Dun, Grant C. Churchill, and Sandip Patel. "Recruitment of NAADP-sensitive acidic Ca2+ stores by glutamate." Biochemical Journal 422, no. 3 (August 27, 2009): 503–12. http://dx.doi.org/10.1042/bj20090194.

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NAADP (nicotinic acid–adenine dinucleotide phosphate) is an unusual second messenger thought to mobilize acidic Ca2+ stores, such as lysosomes or lysosome-like organelles, that are functionally coupled to the ER (endoplasmic reticulum). Although NAADP-sensitive Ca2+ stores have been described in neurons, the physiological cues that recruit them are not known. Here we show that in both hippocampal neurons and glia, extracellular application of glutamate, in the absence of external Ca2+, evoked cytosolic Ca2+ signals that were inhibited by preventing organelle acidification or following osmotic bursting of lysosomes. The sensitivity of both cell types to glutamate correlated well with lysosomal Ca2+ content. However, interfering with acidic compartments was largely without effect on the Ca2+ content of the ER or Ca2+ signals in response to ATP. Glutamate but not ATP elevated cellular NAADP levels. Our results provide evidence for the agonist-specific recruitment of NAADP-sensitive Ca2+ stores by glutamate. This links the actions of NAADP to a major neurotransmitter in the brain.

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Luzio, J. P., N. A. Bright, and P. R. Pryor. "The role of calcium and other ions in sorting and delivery in the late endocytic pathway." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1088–91. http://dx.doi.org/10.1042/bst0351088.

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The passage of endocytosed receptor-bound ligands and membrane proteins through the endocytic pathway of mammalian cells to lysosomes occurs via early and late endosomes. The latter contain many luminal vesicles and are often referred to as MVBs (multivesicular bodies). The overall morphology of endosomal compartments is, in major part, a consequence of the many fusion events occurring in the endocytic pathway. Kissing events and direct fusion between late endosomes and lysosomes provide a means of delivery to lysosomes. The luminal ionic composition of organelles in the endocytic pathway is of considerable importance both in the trafficking of endocytosed ligands and in the membrane fusion events. In particular, H+ ions play a role in sorting processes and providing an appropriate environment for the action of lysosomal acid hydrolases. Na+/H+ exchangers in the endosomal membrane have been implicated in the formation of MVBs and sorting into luminal vesicles. Ca2+ ions are required for fusion events and luminal content condensation in the lysosome. Consistent with an important role for luminal Ca2+ in traffic through the late endocytic pathway, mutations in the gene encoding mucolipin-1, a lysosomal non-specific cation channel, result in abnormalities in lipid traffic and are associated with the autosomal recessive lysosomal storage disease MLIV (mucolipidosis type IV).

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TIEDTKE, A., L. RASMUSSEN, J. FLORIN-CHRISTENSEN, and M. FLORIN-CHRISTENSEN. "Release of lysosomal enzymes in Tetrahymena: a Ca2+-dependent secretory process." Journal of Cell Science 90, no. 1 (May 1, 1988): 167–71. http://dx.doi.org/10.1242/jcs.90.1.167.

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The ciliate Tetrahymena thermophila releases lysosomal enzymes into nutrient and starvation media. We show here that this process occurs selectively, i.e. without leakage of cytoplasmic components, as indicated by lack of release of isocitrate dehydrogenase, a cytosolic enzyme with high activity in Tetrahymena. The role of intracellular Ca2+ in the process was also investigated. The Ca2+ ionophore A23187 has strong stimulatory effects on this release. Ionophore stimulation is maximal in the presence of extracellular Ca2+ but can occur also in its absence. Quin 2 fluorescence measurements indicate that intracellular Ca2+ increases in both cases. Mg2+ completely prevents the stimulatory effects of A23187. Ionomycin, another Ca2+ ionophore, also stimulates lysosomal enzyme release with a maximal response in the presence of extracellular Ca2+. Measurements of extracellular isocitrate dehydrogenase showed that ionophore-stimulated lysosomal enzyme release can take place without leakage of cytoplasmic components. The observations that divalent cation ionophores stimulate selective lysosomal enzyme release and that this effect is strongest in the presence of external Ca2+ indicate that this cation plays a crucial role in the control of this process in Tetrahymena. Together with other observations they support the view that a subpopulation of Tetrahymena lysosomes has properties like those of secretory vesicles.

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Tam, Christina, Vincent Idone, Cecilia Devlin, Maria Cecilia Fernandes, Andrew Flannery, Xingxuan He, Edward Schuchman, Ira Tabas, and Norma W. Andrews. "Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair." Journal of Cell Biology 189, no. 6 (June 7, 2010): 1027–38. http://dx.doi.org/10.1083/jcb.201003053.

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Rapid plasma membrane resealing is essential for cellular survival. Earlier studies showed that plasma membrane repair requires Ca2+-dependent exocytosis of lysosomes and a rapid form of endocytosis that removes membrane lesions. However, the functional relationship between lysosomal exocytosis and the rapid endocytosis that follows membrane injury is unknown. In this study, we show that the lysosomal enzyme acid sphingomyelinase (ASM) is released extracellularly when cells are wounded in the presence of Ca2+. ASM-deficient cells, including human cells from Niemann-Pick type A (NPA) patients, undergo lysosomal exocytosis after wounding but are defective in injury-dependent endocytosis and plasma membrane repair. Exogenously added recombinant human ASM restores endocytosis and resealing in ASM-depleted cells, suggesting that conversion of plasma membrane sphingomyelin to ceramide by this lysosomal enzyme promotes lesion internalization. These findings reveal a molecular mechanism for restoration of plasma membrane integrity through exocytosis of lysosomes and identify defective plasma membrane repair as a possible component of the severe pathology observed in NPA patients.

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Skoupa, Nikola, Petr Dolezel, and Petr Mlejnek. "Lysosomal Fusion: An Efficient Mechanism Increasing Their Sequestration Capacity for Weak Base Drugs without Apparent Lysosomal Biogenesis." Biomolecules 10, no. 1 (January 3, 2020): 77. http://dx.doi.org/10.3390/biom10010077.

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Lysosomal sequestration of anticancer therapeutics lowers their cytotoxic potential, reduces drug availability at target sites, and contributes to cancer resistance. Only recently has it been shown that lysosomal sequestration of weak base drugs induces lysosomal biogenesis mediated by activation of transcription factor EB (TFEB) which, in turn, enhances their accumulation capacity, thereby increasing resistance to these drugs. Here, we addressed the question of whether lysosomal biogenesis is the only mechanism that increases lysosomal sequestration capacity. We found that lysosomal sequestration of some tyrosine kinase inhibitors (TKIs), gefitinib (GF) and imatinib (IM), induced expansion of the lysosomal compartment. However, an expression analysis of lysosomal genes, including lysosome-associated membrane proteins 1, 2 (LAMP1, LAMP2), vacuolar ATPase subunit B2 (ATP6V1B2), acid phosphatase (ACP), and galactosidase beta (GLB) controlled by TFEB, did not reveal increased expression. Instead, we found that both studied TKIs, GF and IM, induced lysosomal fusion which was dependent on nicotinic acid adenine dinucleotide phosphate (NAADP) mediated Ca2+signaling. A theoretical analysis revealed that lysosomal fusion is sufficient to explain the enlargement of lysosomal sequestration capacity. In conclusion, we demonstrated that extracellular TKIs, GF and IM, induced NAADP/Ca2+ mediated lysosomal fusion, leading to enlargement of the lysosomal compartment with significantly increased sequestration capacity for these drugs without apparent lysosomal biogenesis.

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22

Astaburuaga, Rosario, Orlando Daniel Quintanar Haro, Tobias Stauber, and Angela Relógio. "A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl− Transport in Ca2+ Dynamics." Cells 8, no. 10 (October 16, 2019): 1263. http://dx.doi.org/10.3390/cells8101263.

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The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences. Accordingly, several human diseases are caused by the dysfunction of ion transporters. These include osteopetrosis, caused by the dysfunction of Cl−/H+ exchange by the lysosomal transporter ClC-7. To better understand how chloride transport affects lysosomal ion homeostasis and how its disruption impinges on lysosomal function, we developed a mathematical model of lysosomal ion homeostasis including Ca2+ dynamics. The model recapitulates known biophysical properties of ClC-7 and enables the investigation of its differential activation kinetics on lysosomal ion homeostasis. We show that normal functioning of ClC-7 supports the acidification process, is associated with increased luminal concentrations of sodium, potassium, and chloride, and leads to a higher Ca2+ uptake and release. Our model highlights the role of ClC-7 in lysosomal acidification and shows the existence of differential Ca2+ dynamics upon perturbations of Cl−/H+ exchange and its activation kinetics, with possible pathological consequences.

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23

Zimmerli, S., M. Majeed, M. Gustavsson, O. Stendahl, D. A. Sanan, and J. D. Ernst. "Phagosome-lysosome fusion is a calcium-independent event in macrophages." Journal of Cell Biology 132, no. 1 (January 1, 1996): 49–61. http://dx.doi.org/10.1083/jcb.132.1.49.

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Phagosome-lysosome membrane fusion is a highly regulated event that is essential for intracellular killing of microorganisms. Functionally, it represents a form of polarized regulated secretion, which is classically dependent on increases in intracellular ionized calcium ([Ca2+]i). Indeed, increases in [Ca2+]i are essential for phagosome-granule (lysosome) fusion in neutrophils and for lysosomal fusion events that mediate host cell invasion by Trypanosoma cruzi trypomastigotes. Since several intracellular pathogens survive in macrophage phagosomes that do not fuse with lysosomes, we examined the regulation of phagosome-lysosome fusion in macrophages. Macrophages (M phi) were treated with 12.5 microM bis-(2-amino-S-methylphenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethyl ester (MAPT/AM), a cell-permeant calcium chelator which reduced resting cytoplasmic [Ca2+]; from 80 nM to < or = 20 nM and completely blocked increases in [Ca2+]i in response to multiple stimuli, even in the presence of extracellular calcium. Subsequently, M phi phagocytosed serum-opsonized zymosan, staphylococci, or Mycobacterium bovis. Microbes were enumerated by 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI) staining, and phagosome-lysosome fusion was scored using both lysosome-associated membrane protein (LAMP-1) as a membrane marker and rhodamine dextran as a content marker for lysosomes. Confirmation of phagosome-lysosome fusion by electron microscopy validated the fluorescence microscopy findings. We found that phagosome-lysosome fusion in M phi occurs noramlly at very low [Ca2+]i (< or = 20 nM). Kinetic analysis showed that in M phi none of the steps leading from particle binding to eventual phagosome-lysosome fusion are regulated by [Ca2+]i in a rate-limiting way. Furthermore, confocal microscopy revealed no difference in the intensity of LAMP-1 immunofluorescence in phagolysosome membranes in calcium-buffered vs. control macrophages. We conclude that neither membrane recognition nor fusion events in the phagosomal pathway in macrophages are dependent on or regulated by calcium.

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24

Xu, Mengnan, and Xian-Ping Dong. "Endolysosomal TRPMLs in Cancer." Biomolecules 11, no. 1 (January 6, 2021): 65. http://dx.doi.org/10.3390/biom11010065.

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Lysosomes, the degradative endpoints and sophisticated cellular signaling hubs, are emerging as intracellular Ca2+ stores that govern multiple cellular processes. Dys-homeostasis of lysosomal Ca2+ is intimately associated with a variety of human diseases including cancer. Recent studies have suggested that the Ca2+-permeable channels Transient Receptor Potential (TRP) Mucolipins (TRPMLs, TRPML1-3) integrate multiple processes of cell growth, division and metabolism. Dysregulation of TRPMLs activity has been implicated in cancer development. In this review, we provide a summary of the latest development of TRPMLs in cancer. The expression of TRPMLs in cancer, TRPMLs in cancer cell nutrient sensing, TRPMLs-mediated lysosomal exocytosis in cancer development, TRPMLs in TFEB-mediated gene transcription of cancer cells, TRPMLs in bacteria-related cancer development and TRPMLs-regulated antitumor immunity are discussed. We hope to guide readers toward a more in-depth discussion of the importance of lysosomal TRPMLs in cancer progression and other human diseases.

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25

Czibener, Cecilia, Nathan M. Sherer, Steven M. Becker, Marc Pypaert, Enfu Hui, Edwin R. Chapman, Walther Mothes, and Norma W. Andrews. "Ca2+ and synaptotagmin VII–dependent delivery of lysosomal membrane to nascent phagosomes." Journal of Cell Biology 174, no. 7 (September 18, 2006): 997–1007. http://dx.doi.org/10.1083/jcb.200605004.

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Synaptotagmin (Syt) VII is a ubiquitously expressed member of the Syt family of Ca2+ sensors. It is present on lysosomes in several cell types, where it regulates Ca2+-dependent exocytosis. Because [Ca2+]i and exocytosis have been associated with phagocytosis, we investigated the phagocytic ability of macrophages from Syt VII−/− mice. Syt VII−/− macrophages phagocytose normally at low particle/cell ratios but show a progressive inhibition in particle uptake under high load conditions. Complementation with Syt VII rescues this phenotype, but only when functional Ca2+-binding sites are retained. Reinforcing a role for Syt VII in Ca2+-dependent phagocytosis, particle uptake in Syt VII−/− macrophages is significantly less dependent on [Ca2+]i. Syt VII is concentrated on peripheral domains of lysosomal compartments, from where it is recruited to nascent phagosomes. Syt VII recruitment is rapidly followed by the delivery of Lamp1 to phagosomes, a process that is inhibited in Syt VII−/− macrophages. Thus, Syt VII regulates the Ca2+-dependent mobilization of lysosomes as a supplemental source of membrane during phagocytosis.

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26

Lloyd-Evans, Emyr, and Frances M. Platt. "Lysosomal Ca2+ homeostasis: Role in pathogenesis of lysosomal storage diseases." Cell Calcium 50, no. 2 (August 2011): 200–205. http://dx.doi.org/10.1016/j.ceca.2011.03.010.

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27

Caler, Elisabet V., Sabyasachi Chakrabarti, Kimberly T. Fowler, Swathi Rao, and Norma W. Andrews. "The Exocytosis-Regulatory Protein Synaptotagmin VII Mediates Cell Invasion by Trypanosoma cruzi." Journal of Experimental Medicine 193, no. 9 (May 7, 2001): 1097–104. http://dx.doi.org/10.1084/jem.193.9.1097.

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The intracellular protozoan parasite Trypanosoma cruzi causes Chagas' disease, which affects millions of people in Latin America. T. cruzi enters a large number of cell types by an unusual mechanism that involves Ca2+-triggered fusion of lysosomes with the plasma membrane. Here we show that synaptotagmin VII (Syt VII), a ubiquitously expressed synaptotagmin isoform that regulates exocytosis of lysosomes, is localized on the membranes of intracellular vacuoles containing T. cruzi. Antibodies against the C2A domain of Syt VII or recombinant peptides including this domain inhibit cell entry by T. cruzi, but not by Toxoplasma gondii or Salmonella typhimurium. The C2A domains of other ubiquitously expressed synaptotagmin isoforms have no effect on T. cruzi invasion, and mutation of critical residues on Syt VII C2A abolish its inhibitory activity. These findings indicate that T. cruzi exploits the Syt VII–dependent, Ca2+-regulated lysosomal exocytic pathway for invading host cells.

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28

Feng, Xinghua, Zhuangzhuang Zhao, Qian Li, and Zhiyong Tan. "Lysosomal Potassium Channels: Potential Roles in Lysosomal Function and Neurodegenerative Diseases." CNS & Neurological Disorders - Drug Targets 17, no. 4 (July 6, 2018): 261–66. http://dx.doi.org/10.2174/1871527317666180202110717.

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Background & Objective: The lysosome is a membrane-enclosed organelle widely found in every eukaryotic cell. It has been deemed as the stomach of the cells. Recent studies revealed that it also functions as an intracellular calcium store and is a platform for nutrient-dependent signal transduction. Similar with the plasma membrane, the lysosome membrane is furnished with various proteins, including pumps, ion channels and transporters. So far, two types of lysosomal potassium channels have been identified: large-conductance and Ca2+-activated potassium channel (BK) and TMEM175. TMEM175 has been linked to several neurodegeneration diseases, such as the Alzheimer and Parkinson disease. Recent studies showed that TMEM175 is a lysosomal potassium channel with novel architecture and plays important roles in setting the lysosomal membrane potential and maintaining pH stability. TMEM175 deficiency leads to compromised lysosomal function, which might be responsible for the pathogenesis of related diseases. BK is a well-known potassium channel for its function on the plasma membrane. Studies from two independent groups revealed that functional BK channels are also expressed on the lysosomal plasma membrane. Dysfunction of BK causes impaired lysosomal calcium signaling and abnormal lipid accumulation, a featured phenotype of most lysosomal storage diseases (LSDs). Boosting BK activity could rescue the lipid accumulation in several LSD cell models. Overall, the lysosomal potassium channels are essential for the lysosome physiological function, including lysosomal calcium signaling and autophagy. The dysfunction of lysosomal potassium channels is related to some neurodegeneration disorders. Conclusion: Therefore, lysosomal potassium channels are suggested as potential targets for the intervention of lysosomal disorders.

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29

Tedeschi, Petrozziello, and Secondo. "Calcium Dyshomeostasis and Lysosomal Ca2+ Dysfunction in Amyotrophic Lateral Sclerosis." Cells 8, no. 10 (October 8, 2019): 1216. http://dx.doi.org/10.3390/cells8101216.

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Recent findings in the understanding of amyotrophic lateral sclerosis (ALS) revealed that alteration in calcium (Ca2+) homeostasis may largely contribute to motor neuron demise. A large part of these alterations is due to dysfunctional Ca2+-storing organelles, including the endoplasmic reticulum (ER) and mitochondria. Very recently, lysosomal Ca2+ dysfunction has emerged as an important pathological change leading to neuronal loss in ALS. Remarkably, the Ca2+-storing organelles are interacting with each other at specialized domains controlling mitochondrial dynamics, ER/lysosomal function, and autophagy. This occurs as a result of interaction between specific ionic channels and Ca2+-dependent proteins located in each structure. Therefore, the dysregulation of these ionic mechanisms could be considered as a key element in the neurodegenerative process. This review will focus on the possible role of lysosomal Ca2+ dysfunction in the pathogenesis of several neurodegenerative diseases, including ALS and shed light on the possibility that specific lysosomal Ca2+ channels might represent new promising targets for preventing or at least delaying neurodegeneration in ALS.

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30

Jha, Archana, Eugen Brailoiu, and Shmuel Muallem. "How does NAADP release lysosomal Ca2+?" Channels 8, no. 3 (May 2014): 174–75. http://dx.doi.org/10.4161/chan.28995.

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31

Tancini, Brunella, Sandra Buratta, Federica Delo, Krizia Sagini, Elisabetta Chiaradia, Roberto Maria Pellegrino, Carla Emiliani, and Lorena Urbanelli. "Lysosomal Exocytosis: The Extracellular Role of an Intracellular Organelle." Membranes 10, no. 12 (December 9, 2020): 406. http://dx.doi.org/10.3390/membranes10120406.

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Lysosomes are acidic cell compartments containing a large set of hydrolytic enzymes. These lysosomal hydrolases degrade proteins, lipids, polysaccharides, and nucleic acids into their constituents. Materials to be degraded can reach lysosomes either from inside the cell, by autophagy, or from outside the cell, by different forms of endocytosis. In addition to their degradative functions, lysosomes are also able to extracellularly release their contents by lysosomal exocytosis. These organelles move from the perinuclear region along microtubules towards the proximity of the plasma membrane, then the lysosomal and plasma membrane fuse together via a Ca2+-dependent process. The fusion of the lysosomal membrane with plasma membrane plays an important role in plasma membrane repair, while the secretion of lysosomal content is relevant for the remodelling of extracellular matrix and release of functional substrates. Lysosomal storage disorders (LSDs) and age-related neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases, share as a pathological feature the accumulation of undigested material within organelles of the endolysosomal system. Recent studies suggest that lysosomal exocytosis stimulation may have beneficial effects on the accumulation of these unprocessed aggregates, leading to their extracellular elimination. However, many details of the molecular machinery required for lysosomal exocytosis are only beginning to be unravelled. Here, we are going to review the current literature on molecular mechanisms and biological functions underlying lysosomal exocytosis, to shed light on the potential of lysosomal exocytosis stimulation as a therapeutic approach.

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32

Morgan, Anthony J., Frances M. Platt, Emyr Lloyd-Evans, and Antony Galione. "Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease." Biochemical Journal 439, no. 3 (October 13, 2011): 349–78. http://dx.doi.org/10.1042/bj20110949.

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Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

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33

Cook, Sophie R., Rafael A. Badell-Grau, Emily D. Kirkham, Kimberley M. Jones, Brendan P. Kelly, Jincy Winston, Helen Waller-Evans, Nicholas D. Allen, and Emyr Lloyd-Evans. "Detrimental effect of zwitterionic buffers on lysosomal homeostasis in cell lines and iPSC-derived neurons." AMRC Open Research 2 (May 18, 2020): 21. http://dx.doi.org/10.12688/amrcopenres.12903.1.

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Good’s buffers are commonly used for cell culture and, although developed to have minimal to no biological impact, they cause alterations in cellular processes such as autophagy and lysosomal enzyme activity. Using Chinese hamster ovary cells and induced pluripotent stem cell-derived neurons, this study explores the effect of zwitterionic buffers, specifically HEPES, on lysosomal volume and Ca2+ levels. Certain zwitterionic buffers lead to lysosomal expansion and reduced lysosomal Ca2+. Care should be taken when selecting buffers for growth media to avoid detrimental impacts on lysosomal function.

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34

HALLER, Thomas, Harald VÖLKL, Peter DEETJEN, and Paul DIETL. "The lysosomal Ca2+ pool in MDCK cells can be released by ins(1,4,5)P3-dependent hormones or thapsigargin but does not activate store-operated Ca2+ entry." Biochemical Journal 319, no. 3 (November 1, 1996): 909–12. http://dx.doi.org/10.1042/bj3190909.

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In several cell types, Ca2+ release from intracellular Ca2+ stores by Ins(1,4,5)P3 elicits Ca2+ influx from the extracellular space into the cytoplasm, termed store-operated Ca2+ entry (SOCE). In MDCK cells, the Ins(1,4,5)P3-sensitive Ca2+ store giving rise to SOCE essentially overlaps with the thapsigargin (TG)-sensitive store. Recent evidence suggests that in MDCK cells lysosomes form a Ca2+ pool that is functionally coupled with the Ins(1,4,5)P3-sensitive Ca2+ store: Ca2+ can be selectively released from lysosomes by glycyl-L-phenylalanine naphthylamide, an agent inducing lysosomal swelling with subsequent and reversible permeabilization of the vesicular membranes. This compartment is also depleted by Ins(1,4,5)P3-dependent agonists or TG, indicating that it is part of a larger, Ins(1,4,5)P3-sensitive Ca2+ pool. Here we show that whereas SOCE is triggered by Ca2+ release from the entire Ins(1,4,5)P3-sensitive Ca2+ pool, selective Ca2+ release from lysosomes alone is unable to trigger SOCE. This finding is consistent with measurements of the store-operated cation current, a direct parameter for store-operated Ca2+ and Na+ entry into MDCK cells. Hence it is proposed that the Ins(1,4,5)P3-sensitive Ca2+ pool is composed of different intracellular compartments that do not uniformly stimulate Ca2+ entry into the cell.

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Thomas, Diana D. H., Christina L. Martin, Ning Weng, Jennifer A. Byrne, and Guy E. Groblewski. "Tumor protein D52 expression and Ca2+-dependent phosphorylation modulates lysosomal membrane protein trafficking to the plasma membrane." American Journal of Physiology-Cell Physiology 298, no. 3 (March 2010): C725—C739. http://dx.doi.org/10.1152/ajpcell.00455.2009.

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Tumor protein D52 (also known as CRHSP-28) is highly expressed in multiple cancers and tumor-derived cell lines; however, it is normally abundant in secretory epithelia throughout the digestive system, where it has been implicated in Ca2+-dependent digestive enzyme secretion ( 41 ). Here we demonstrate, using site-specific mutations, that Ca2+-sensitive phosphorylation at serine 136 modulates the accumulation of D52 at the plasma membrane within 2 min of cell stimulation. When expressed in Chinese hamster ovary CHO-K1 cells, D52 colocalized with adaptor protein AP-3, Rab27A, vesicle-associated membrane protein VAMP7, and lysosomal-associated membrane protein LAMP1, all of which are present in lysosome-like secretory organelles. Overexpression of D52 resulted in a marked accumulation of LAMP1 on the plasma membrane that was further enhanced following elevation of cellular Ca2+. Strikingly, mutation of serine 136 to alanine abolished the Ca2+-stimulated accumulation of LAMP1 at the plasma membrane whereas phosphomimetic mutants constitutively induced LAMP1 plasma membrane accumulation independent of elevated Ca2+. Identical results were obtained for endogenous D52 in normal rat kidney and HeLA cells, where both LAMP1 and D52 rapidly accumulated on the plasma membrane in response to elevated cellular Ca2+. Finally, D52 induced the uptake of LAMP1 antibodies from the cell surface in accordance with both the level of D52 expression and phosphorylation at serine 136 demonstrating that D52 altered the plasma membrane recycling of LAMP1-associated secretory vesicles. These findings implicate both D52 expression and Ca2+-dependent phosphorylation at serine 136 in lysosomal membrane trafficking to and from the plasma membrane providing a novel Ca2+-sensitive pathway modulating the lysosome-like secretory pathway.

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Huterer, Srebrenka J., and John R. Wherrett. "Formation of acylphosphatidylglycerol by a lysosomal phosphatidylcholine: bis(monoacylglycero)phosphate acyl transferase." Biochemistry and Cell Biology 68, no. 1 (January 1, 1990): 366–72. http://dx.doi.org/10.1139/o90-050.

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A delipidated soluble fraction prepared from a mitochondrial–lysosomal fraction of rabbit alveolar macrophages that catalyzes transacylation of lysophosphatidylglycerol to form bis(monoacylglycero)phosphate was also found to transfer oleic acid from [14C]dioleoyl phosphatidylcholine to form acylphosphatidylglycerol. The reaction was dependent on the presence of bis(monoacylglycero)phosphate and was maximal at a concentration of 44 μM when the ratio of fatty acid transferred to fatty acid released was 0.28. Addition of phosphatidylglycerol had only a small effect. Homogenates of rat liver also catalyzed the reaction and after subcellular fractionation the activity was localized to lysosomes. The lysosomal activity was solubilized by delipidation with butanol to give a preparation with a specific activity 2462 times that of the homogenate. Optimal activity of soluble preparations from both macrophages and liver was at pH 4.5, with little activity above 6.0. Release of free fatty acid was also stimulated under conditions of optimal acyl transfer. Both acyl transfer and release of fatty acid were inhibited by Ca2+, detergents, chlorpromazine, lysophosphatidylcholine, and oleic acid. Where there was disproportional inhibition, acyl transfer was always more affected. These results suggest that sequential acylation of lysophosphatidylglycerol to form bis(monoacylglycero)phosphate and then acylphosphatidylglycerol constitute a mechanism in the lysosome for the transport and partition of fatty acids released by the lysosomal phospholipases.Key words: acylphosphatidylglycerol, bis(monoacylglycero)phosphate, transacylase, lysosomes, macrophages.

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37

Zhang, Fan, Guo Zhang, Andrew Y. Zhang, Matthew J. Koeberl, Eryn Wallander, and Pin-Lan Li. "Production of NAADP and its role in Ca2+ mobilization associated with lysosomes in coronary arterial myocytes." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 1 (July 2006): H274—H282. http://dx.doi.org/10.1152/ajpheart.01064.2005.

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The present study was designed to determine the production of nicotinic acid adenine dinucleotide phosphate (NAADP) and its role associated with lysosomes in mediating endothelin-1 (ET-1)-induced vasoconstriction in coronary arteries. HPLC assay showed that NAADP was produced in coronary arterial smooth muscle cells (CASMCs) via endogenous ADP-ribosyl cyclase. Fluorescence microscopic analysis of intracellular Ca2+ concentration ([Ca2+]i) in CASMCs revealed that exogenous 100 nM NAADP increased [Ca2+]i by 711 ± 47 nM. Lipid bilayer experiments, however, demonstrated that NAADP did not directly activate ryanodine (Rya) receptor Ca2+ release channels on the sarcoplasmic reticulum. In CASMCs pretreated with 100 nM bafilomycin A1 (Baf), an inhibitor of lysosomal Ca2+ release and vacuolar proton pump function, NAADP-induced [Ca2+]i increase was significantly abolished. Moreover, ET-1 significantly increased NAADP formation in CASMCs and resulted in the rise of [Ca2+]i in these cells with a large increase in global Ca2+ level of 1,815 ± 84 nM. Interestingly, before this large Ca2+ increase, a small Ca2+ spike with an increase in [Ca2+]i of 529 ± 32 nM was observed. In the presence of Baf (100 nM), this ET-1-induced two-phase [Ca2+]i response was completely abolished, whereas Rya (50 μM) only markedly blocked the ET-1-induced large global Ca2+ increase. Functional studies showed that 100 nM Baf significantly attenuated ET-1-induced maximal constriction from 82.26 ± 4.42% to 51.80 ± 4.36%. Our results suggest that a lysosome-mediated Ca2+ regulatory mechanism via NAADP contributes to ET-1-induced Ca2+ mobilization in CASMCs and consequent vasoconstriction of coronary arteries.

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Tsukamoto, Osamu, Hiroshi Asanuma, and Masafumi Kitakaze. "Targeting lysosomal Ca2+to reduce reperfusion injury." Cardiovascular Research 108, no. 3 (October 23, 2015): 321–23. http://dx.doi.org/10.1093/cvr/cvv242.

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39

KISELYOV, K., and S. MUALLEM. "Mitochondrial Ca2+ homeostasis in lysosomal storage diseases." Cell Calcium 44, no. 1 (July 2008): 103–11. http://dx.doi.org/10.1016/j.ceca.2007.12.005.

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40

Kiselyov, Kirill, Soichiro Yamaguchi, Christopher W. Lyons, and Shmuel Muallem. "Aberrant Ca2+ handling in lysosomal storage disorders." Cell Calcium 47, no. 2 (February 2010): 103–11. http://dx.doi.org/10.1016/j.ceca.2009.12.007.

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41

Cao, Qi, Yiming Yang, Xi Zoë Zhong, and Xian-Ping Dong. "The lysosomal Ca2+ release channel TRPML1 regulates lysosome size by activating calmodulin." Journal of Biological Chemistry 292, no. 20 (March 30, 2017): 8424–35. http://dx.doi.org/10.1074/jbc.m116.772160.

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42

Yang, Yiming, Mengnan Xu, Xiaojuan Zhu, Jing Yao, Bing Shen, and Xian-Ping Dong. "Lysosomal Ca2+ release channel TRPML1 regulates lysosome size by promoting mTORC1 activity." European Journal of Cell Biology 98, no. 2-4 (June 2019): 116–23. http://dx.doi.org/10.1016/j.ejcb.2019.05.001.

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43

Eeckhout, Y. "Possible role and mechanism of action of dissolved calcium in the degradation of bone collagen by lysosomal cathepsins and collagenase." Biochemical Journal 272, no. 2 (December 1, 1990): 529–32. http://dx.doi.org/10.1042/bj2720529.

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Equilibrium experiments with bone powder, at pH values ranging from 6.3 to 3.5, show a linear relation between log([Ca2+]/[Ca2+]0) (where [Ca2+]0 = 1 M-Ca2+) and pH, indicating that [Ca2+] could reach levels of 25 mM at pH 5 and 90 mM at pH 4. These elevated Ca2+ concentrations stimulated the lysis of insoluble bone collagen in vitro by purified lysosomes and by mouse bone collagenase, whose activities were additive at acid pH. At neutral pH, the addition of 10-100 mM-CaCl2 did not influence the susceptibility of acid-soluble skin collagen in solution towards bone collagenase, but increased it markedly towards collagen in the fibrillar form. Increasing the [Ca2+] did not influence the susceptibility of collagen to trypsin. Elevated [Ca2+] and a co-operation between lysosomal cysteine proteinases and matrix collagenase could thus participate in the osteoclastic breakdown of bone collagen.

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44

Kutryk, Michael J. B., and Naranjan S. Dhalla. "Alterations in cardiac lysosomal hydrolases following induction of the calcium paradox." Canadian Journal of Physiology and Pharmacology 65, no. 11 (November 1, 1987): 2175–81. http://dx.doi.org/10.1139/y87-343.

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Although perfusion of the heart with calcium-free medium for a brief period followed by reperfusion with calcium-containing medium results in marked structural derangements (calcium paradox), the mechanisms for this cell damage are far from clear. Since activation of lysosomal enzymes has been associated with pathological damage, it was the purpose of this study to examine alterations in the activities of several lysosomal enzymes in rat hearts subjected to calcium paradox. No significant changes in the activities of (β-acetylglucosaminidase, β-galactosidase, α-mannosidase, or acid phosphatase were seen in the homogenates of hearts exposed to the calcium paradox. However, there were dramatic alterations in the lysosomal enzyme activities in the sedimentable and nonsedimentable fractions during calcium paradox. The lysosomal enzyme activities were also detected in the perfusate collected during reperfusion with calcium-containing medium. These changes occurred during the reperfusion period since no alterations were apparent after calcium-free perfusion and were dependent upon the time of reperfusion with medium containing Ca2+ as well as the time of perfusion with Ca2+ -free medium before inducing Ca2+ paradox. These data indicate that alterations in lysosomal enzymes owing to reinstitution of calcium in Ca2+-deprived hearts may occur as a part of cardiac damage and general cellular disintegration.

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Lloyd-Evans, Emyr. "On the move, lysosomal CAX drives Ca2+ transport and motility." Journal of Cell Biology 212, no. 7 (March 28, 2016): 755–57. http://dx.doi.org/10.1083/jcb.201603037.

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Acidic Ca2+ stores are important sources of Ca2+ during cell signaling but little is known about how Ca2+ enters these stores. In this issue, Melchionda et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510019) identify a Ca2+/H+ exchanger (CAX) that is required for Ca2+ uptake and cell migration in vertebrates.

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Morgan, Anthony J., Lianne C. Davis, Siegfried K. T. Y. Wagner, Alexander M. Lewis, John Parrington, Grant C. Churchill, and Antony Galione. "Bidirectional Ca2+ signaling occurs between the endoplasmic reticulum and acidic organelles." Journal of Cell Biology 200, no. 6 (March 11, 2013): 789–805. http://dx.doi.org/10.1083/jcb.201204078.

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The endoplasmic reticulum (ER) and acidic organelles (endo-lysosomes) act as separate Ca2+ stores that release Ca2+ in response to the second messengers IP3 and cADPR (ER) or NAADP (acidic organelles). Typically, trigger Ca2+ released from acidic organelles by NAADP subsequently recruits IP3 or ryanodine receptors on the ER, an anterograde signal important for amplification and Ca2+ oscillations/waves. We therefore investigated whether the ER can signal back to acidic organelles, using organelle pH as a reporter of NAADP action. We show that Ca2+ released from the ER can activate the NAADP pathway in two ways: first, by stimulating Ca2+-dependent NAADP synthesis; second, by activating NAADP-regulated channels. Moreover, the differential effects of EGTA and BAPTA (slow and fast Ca2+ chelators, respectively) suggest that the acidic organelles are preferentially activated by local microdomains of high Ca2+ at junctions between the ER and acidic organelles. Bidirectional organelle communication may have wider implications for endo-lysosomal function as well as the generation of Ca2+ oscillations and waves.

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Zou, J., B. Hu, S. Arpag, Q. Yan, A. Hamilton, Y. S. Zeng, C. G. Vanoye, and J. Li. "Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells." Journal of Neuroscience 35, no. 17 (April 29, 2015): 6801–12. http://dx.doi.org/10.1523/jneurosci.4442-14.2015.

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Lindley, E. R., and R. L. Pisoni. "Demonstration of adenosine deaminase activity in human fibroblast lysosomes." Biochemical Journal 290, no. 2 (March 1, 1993): 457–62. http://dx.doi.org/10.1042/bj2900457.

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Human fibroblast lysosomes, purified on Percoll density gradients, contain an adenosine deaminase (ADA) activity that accounts for approximately 10% of the total ADA activity in GM0010A human fibroblasts. In assays of lysosomal ADA, the conversion of [3H]adenosine into [3H]inosine was proportional to incubation time and the amount of lysosomal material added to reaction mixtures. Maximal activity was observed between pH 7 and 8, and lysosomal ADA displayed a Km of 37 microM for adenosine at 25 degrees C and pH 5.5. Lysosomal ADA was completely inhibited by 2.5 mM Cu2+ or Hg2+ salts, but not by other bivalent cations (Ba2+, Cd2+, Ca2+, Fe2+, Mg2+, Mn2+ and Zn2+). Coformycin (2.5 mM), deoxycoformycin (0.02 mM), 2′-deoxyadenosine (2.5 mM), 6-methylaminopurine riboside (2.5 mM), 2′-3′-isopropylidene-adenosine (2.5 mM) and erythro-9-(2-hydroxy-3-nonyl)adenine (0.2 mM) inhibited lysosomal ADA by > 97%. In contrast, 2.5 mM S-adenosyl-L-homocysteine and cytosine were poor inhibitors. Nearly all lysosomal ADA activity is eluted as a high-molecular-mass protein (> 200 kDa) just after the void volume on a Sephacryl S-200 column, and is very heat-stable, retaining 70% of its activity after incubation at 65 degrees C for 80 min. We speculate that compartmentalization of ADA within lysosomes would allow deamination of adenosine to occur without competition by adenosine kinase, which could assist in maintaining cellular energy requirements under conditions of nutritional deprivation.

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Patel, Sandip. "Deviant Lysosomal Ca2+ Signalling in Neurodegeneration. An Introduction." Messenger 5, no. 1 (June 1, 2016): 24–29. http://dx.doi.org/10.1166/msr.2016.1053.

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Galione, Antony, Anthony J. Morgan, Abdelilah Arredouani, Lianne C. Davis, Katja Rietdorf, Margarida Ruas, and John Parrington. "NAADP as an intracellular messenger regulating lysosomal calcium-release channels." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1424–31. http://dx.doi.org/10.1042/bst0381424.

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Recent studies into the mechanisms of action of the Ca2+-mobilizing messenger NAADP (nicotinic acid–adenine dinucleotide phosphate) have demonstrated that a novel family of intracellular Ca2+-release channels termed TPCs (two-pore channels) are components of the NAADP receptor. TPCs appear to be exclusively localized to the endolysosomal system. These findings confirm previous pharmacological and biochemical studies suggesting that NAADP targets acidic Ca2+ stores rather than the endoplasmic reticulum, the major site of action of the other two principal Ca2+-mobilizing messengers, InsP3 and cADPR (cADP-ribose). Studies of the messenger roles of NAADP and the function of TPCs highlight the novel role of lysosomes and other organelles of the endocytic pathway as messenger-regulated Ca2+ stores which also affects the regulation of the endolysosomal system.

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Journal articles on the topic 'Ca2+ lysosomal'

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